Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor

  • Nat Commun. 2026 Jun 5. doi: 10.1038/s41467-026-73146-5.
Daniel A Rodrigues  1  2 ,  Yu Wang  #  3  4 ,  Juana Goulart Stollmaier  #  5 ,  Graeme P Sullivan  #  3  6 ,  Cian D'Arcy  3 ,  Aisling Y Coughlan  7 ,  Andrew Roe  3 ,  Linda Bíró  8 ,  Paris R Watson  5 ,  Jeremy D Osko  5 ,  Brendan Twamley  9 ,  Kieran Wynne  10  11 ,  Gerard Cagney  10 ,  Péter Buglyó  8 ,  Yanli Liu  4 ,  Darren M Griffith  12  13 ,  David W Christianson  5 ,  Tríona Ní Chonghaile  14  15
Affiliations
  • 1. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. [email protected].
  • 2. School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland. [email protected].
  • 3. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
  • 4. Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu, China.
  • 5. Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, US.
  • 6. School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
  • 7. School of Medicine, University College Dublin, Dublin 4, Ireland.
  • 8. Department of Inorganic & Analytical Chemistry, Faculty of Science and Technology, University of Debrecen, Debrecen, Egyetem tér 1, Hungary.
  • 9. School of Chemistry, Trinity College Dublin, College Green, Dublin 2, Ireland.
  • 10. School of Biomolecular and Biomedical Science, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland.
  • 11. Systems Biology Ireland, School of Medicine, University College Dublin, Dublin, Ireland.
  • 12. Department of Chemistry, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
  • 13. SSPC, the Taighde Éireann- Research Ireland Centre for Pharmaceuticals, Limerick, Ireland.
  • 14. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. [email protected].
  • 15. Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland. [email protected].
  • # Contributed equally.
PMID: 42248829 DOI: 10.1038/s41467-026-73146-5
Abstract

Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that deacetylates non-histone substrates such as α-tubulin and cortactin. HDAC6 contains two catalytic domains, each containing a catalytic zinc ion, and a zinc-finger ubiquitin-binding domain. We have discovered BAS-2, a selective HDAC6 Inhibitor with an isothiouronium core and no obvious zinc-binding group. To define its mechanism, we combine X-ray crystallography, structure-activity-relationships, molecular modeling and mutagenesis. BAS-2 potently inhibits human HDAC6 but it does not inhibit zebrafish HDAC6. Computational modeling highlighted Asp567 in human HDAC6 as critical for BAS-2 recognition and mutational analyses confirmed this. The corresponding zebrafish residue is Asn530 and the crystal structure of the N530D variant zHDAC6 revealed binding of a BAS-2-derived mercaptoacetamide that engages the catalytic zinc via strong thiolate-zinc coordination. Leveraging the orientation of BAS-2 binding, we designed a BAS-2-based proteolysis targeting chimera that induced proteasome-dependent HDAC6 degradation in cells, verified by global proteomics. Collectively, these insights clarify species selectivity and demonstrate that BAS-2 acts as a selective, mechanism-based inhibitor of human HDAC6. These discoveries will aid the development of the next generation of selective HDAC6 inhibitors and degraders.

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